X-139740994-A-G

Variant names:

• chrX-139740994-A-G
• rs1348871617
• NM_001353812.2:c.3131T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001353812.2(ATP11C):​c.3131T>C​(p.Ile1044Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000679 in 1,177,551 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000047 (0 hom. 1 hem.)
• Consequence: ATP11C NM_001353812.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.89

Genes affected

ATP11C (HGNC:13554): (ATPase phospholipid transporting 11C) Enables phosphatidylethanolamine flippase activity and phosphatidylserine flippase activity. Predicted to be involved in phospholipid translocation; positive regulation of B cell differentiation; and pre-B cell differentiation. Located in endoplasmic reticulum and plasma membrane. Is integral component of plasma membrane. Implicated in X-linked congenital hemolytic anemia. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP11C	NM_001353812.2	c.3131T>C	p.Ile1044Thr	missense_variant	Exon 27 of 30	ENST00000682941.1	NP_001340741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP11C	ENST00000682941.1	c.3131T>C	p.Ile1044Thr	missense_variant	Exon 27 of 30		NM_001353812.2	ENSP00000507250.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111736 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000551 AC: 1 AN: 181397 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000469 AC: 5 AN: 1065815 Hom.: 0 Cov.: 24 AF XY: 0.00000296 AC XY: 1 AN XY: 337999

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25719

American (AMR) AF: 0.00 AC: 0 AN: 34982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19110

East Asian (EAS) AF: 0.00 AC: 0 AN: 30067

South Asian (SAS) AF: 0.00 AC: 0 AN: 53246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40447

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4043

European-Non Finnish (NFE) AF: 0.00000615 AC: 5 AN: 813237

Other (OTH) AF: 0.00 AC: 0 AN: 44964

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000002), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111736 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 33962

African (AFR) AF: 0.00 AC: 0 AN: 30770

American (AMR) AF: 0.00 AC: 0 AN: 10510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.00 AC: 0 AN: 2663

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53121

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3140T>C (p.I1047T) alteration is located in exon 27 (coding exon 27) of the ATP11C gene. This alteration results from a T to C substitution at nucleotide position 3140, causing the isoleucine (I) at amino acid position 1047 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.7	.;M;M;.
PhyloP100		8.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	N;N;N;D
REVEL	Uncertain	0.35
Sift	Benign	0.036	D;D;D;D
Sift4G	Benign	0.066	T;T;T;D
Polyphen		0.94, 0.97	.;P;D;.
Vest4		0.66
MutPred		0.54		.;Loss of catalytic residue at I1047 (P = 0.0222);Loss of catalytic residue at I1047 (P = 0.0222);.;
MVP		0.82
MPC		1.2
ClinPred		0.81	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.86
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs1348871617; hg19: chrX-138823153;